The size and weight of a baby at birth are important determinants of its survival and future health across the life course. Although multiple factors influence birth weight and size, air pollution exposure during pregnancy has been recently explored as a contributor. Millions of women are exposed to ambient air pollution, and levels can be especially high in developing countries. Reducing infant mortality is one of the Millennium Development Goals, so the public health importance of understanding and minimizing environmental contributors to poor birth outcomes is great. Most published epidemiology studies are based on population birth registries and lack the individual, clinical data and repeated measures needed to elucidate possible biological mechanisms mediating epidemiological associations between pollution and adverse birth outcomes. This proposed work presents a unique opportunity to study those mechanisms in a new cohort of 800 pregnant women residing in diverse regions of Mexico City, a mega-city with high air pollution levels. We will investigate how air pollution and the polycyclic aromatic hydrocarbon (PAH) component of particles can influence the outcome of pregnancy, and whether certain periods of gestation represent critical time windows and opportunities for preventive intervention. We will obtain biomarkers relevant to PAH exposure (DNA adducts) in blood samples provided by participants monthly during their pregnancies, and umbilical cord blood obtained at birth. We will also collect information on health history, clinical characteristics, tobacco smoke exposure, diet and time-activity patterns. Simultaneously, we will estimate spatial and temporal variability in air pollution exposure with data from the Mexico City Metropolitan Area (MCMA) air quality monitoring network (PM2.5, PM10, ozone, nitrogen dioxide, sulfur dioxide, carbon monoxide), matched to the exact locations of participants' homes. DNA samples from mother and infant will be used to type genetic polymorphisms (CYP1A1, GSTM1, GSTT1, GSTP1, Xrcc1, XPD) relevant to the hypothesized mechanisms. We will evaluate whether ambient pollution and PAH adducts are associated with three outcomes: birth weight, head circumference and birth length, controlling for other risk factors, and which time windows are most relevant. We will examine effect modification by intake of antioxidant vitamins (E and C) and the genetic polymorphisms. Finally, we will complement this epidemiological study with a parallel toxicology in-vitro study which will involve collecting and characterizing air pollution particle samples (PM10 and PM2.5) on a monthly basis from five zones in MCMA and exposing a monocytic cell line (J774A.1) to evaluate PAH adducts. Any coherence between the human and in vitro evidence for a mechanistic association between pollution and these adducts will guide future studies. This multi-disciplinary, global health collaboration will evaluate potential environmental determinants of adverse birth outcomes, using a novel approach combining epidemiology and toxicology, with the goal of developing unique knowledge with far-reaching prevention implications. PUBLIC HEALTH RELEVANCE This research investigates how air pollution influences the risk of adverse birth outcomes, with a focus on understanding mechanisms and critical time windows of exposure. The goal is to develop knowledge to support 1) policy-makers who set and enforce health-protective air pollution standards; 2) scientists involved in multi-disciplinary studies to understand environmental contributions to infant health, and 3) clinicians interested in prevention of adverse birth outcomes.